Abstract
We examined the insulin dose-response characteristics of human muscle glycogen synthase and phosphorylase activation. We also determined whether increasing the rate of glucose disposal by hyperglycemia at a fixed insulin concentration activates glycogen synthase. Physiological increments in plasma insulin but not glucose increased the fractional activity of glycogen synthase. The ED50: s for insulin stimulation of whole body and forearm glucose disposal were similar and unaffected by glycemia. Glycogen synthase activation was exponentially related to the insulin-mediated component of whole body and forearm glucose disposal at each glucose concentration. Neither insulin nor glucose changed glycogen phosphorylase activity. These results suggest that insulin but not the rate of glucose disposal per se regulates glycogen synthesis by a mechanism that involves dephosphorylation of glycogen synthase but not phosphorylase. This implies that the low glycogen synthase activities found in insulin-resistant states are a consequence of impaired insulin action rather than reduced glucose disposal.
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- Abumrad N. N., Rabin D., Diamond M. P., Lacy W. W. Use of a heated superficial hand vein as an alternative site for the measurement of amino acid concentrations and for the study of glucose and alanine kinetics in man. Metabolism. 1981 Sep;30(9):936–940. doi: 10.1016/0026-0495(81)90074-3. [DOI] [PubMed] [Google Scholar]
- Bergman R. N., Finegood D. T., Ader M. Assessment of insulin sensitivity in vivo. Endocr Rev. 1985 Winter;6(1):45–86. doi: 10.1210/edrv-6-1-45. [DOI] [PubMed] [Google Scholar]
- Best J. D., Judzewitsch R. G., Pfeifer M. A., Beard J. C., Halter J. B., Porte D., Jr The effect of chronic sulfonylurea therapy on hepatic glucose production in non-insulin-dependent diabetes. Diabetes. 1982 Apr;31(4 Pt 1):333–338. doi: 10.2337/diab.31.4.333. [DOI] [PubMed] [Google Scholar]
- Bogardus C., Lillioja S., Mott D., Reaven G. R., Kashiwagi A., Foley J. E. Relationship between obesity and maximal insulin-stimulated glucose uptake in vivo and in vitro in Pima Indians. J Clin Invest. 1984 Mar;73(3):800–805. doi: 10.1172/JCI111274. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bogardus C., Lillioja S., Stone K., Mott D. Correlation between muscle glycogen synthase activity and in vivo insulin action in man. J Clin Invest. 1984 Apr;73(4):1185–1190. doi: 10.1172/JCI111304. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bogardus C., Thuillez P., Ravussin E., Vasquez B., Narimiga M., Azhar S. Effect of muscle glycogen depletion on in vivo insulin action in man. J Clin Invest. 1983 Nov;72(5):1605–1610. doi: 10.1172/JCI111119. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1006/abio.1976.9999. [DOI] [PubMed] [Google Scholar]
- COLES D. R., COOPER K. E., MOTTRAM R. F., OCCLESHAW J. V. The source of blood samples withdrawn from deep forearm veins via catheters passed upstream from the median cubital vein. J Physiol. 1958 Jul 14;142(2):323–328. doi: 10.1113/jphysiol.1958.sp006019. [DOI] [PMC free article] [PubMed] [Google Scholar]
- COOPER K. E., EDHOLM O. G., MOTTRAM R. F. The blood flow in skin and muscle of the human forearm. J Physiol. 1955 May 27;128(2):258–267. doi: 10.1113/jphysiol.1955.sp005304. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chiasson J. L., Dietz M. R., Shikama H., Wootten M., Exton J. H. Insulin regulation of skeletal muscle glycogen metabolism. Am J Physiol. 1980 Jul;239(1):E69–E74. doi: 10.1152/ajpendo.1980.239.1.E69. [DOI] [PubMed] [Google Scholar]
- Craig J. W., Rall T. W., Larner J. The influence of insulin and epinephrine on adenosine 3',5'-phosphate and glycogen transferase in muscle. Biochim Biophys Acta. 1969 Apr 1;177(2):213–219. doi: 10.1016/0304-4165(69)90130-5. [DOI] [PubMed] [Google Scholar]
- DeFronzo R. A., Jacot E., Jequier E., Maeder E., Wahren J., Felber J. P. The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes. 1981 Dec;30(12):1000–1007. doi: 10.2337/diab.30.12.1000. [DOI] [PubMed] [Google Scholar]
- DeFronzo R. A., Tobin J. D., Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979 Sep;237(3):E214–E223. doi: 10.1152/ajpendo.1979.237.3.E214. [DOI] [PubMed] [Google Scholar]
- DeLean A., Munson P. J., Rodbard D. Simultaneous analysis of families of sigmoidal curves: application to bioassay, radioligand assay, and physiological dose-response curves. Am J Physiol. 1978 Aug;235(2):E97–102. doi: 10.1152/ajpendo.1978.235.2.E97. [DOI] [PubMed] [Google Scholar]
- Dillon R. S. Importance of the hematocrit in interpretation of blood sugar. Diabetes. 1965 Oct;14(10):672–674. doi: 10.2337/diab.14.10.672. [DOI] [PubMed] [Google Scholar]
- Ferrannini E., Smith J. D., Cobelli C., Toffolo G., Pilo A., DeFronzo R. A. Effect of insulin on the distribution and disposition of glucose in man. J Clin Invest. 1985 Jul;76(1):357–364. doi: 10.1172/JCI111969. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gilboe D. P., Nuttall F. Q. The role of ATP and glucose 6-phosphate in the regulation of glycogen synthetase D phosphatase. Biochem Biophys Res Commun. 1972 Aug 21;48(4):898–906. doi: 10.1016/0006-291x(72)90693-6. [DOI] [PubMed] [Google Scholar]
- Gottesman I., Mandarino L., Gerich J. Estimation and kinetic analysis of insulin-independent glucose uptake in human subjects. Am J Physiol. 1983 Jun;244(6):E632–E635. doi: 10.1152/ajpendo.1983.244.6.E632. [DOI] [PubMed] [Google Scholar]
- Guinovart J. J., Salavert A., Massagué J., Ciudad C. J., Salsas E., Itarte E. Glycogen synthase: a new activity ratio assay expressing a high sensitivity to the phosphorylation state. FEBS Lett. 1979 Oct 15;106(2):284–288. doi: 10.1016/0014-5793(79)80515-3. [DOI] [PubMed] [Google Scholar]
- Herbert V., Lau K. S., Gottlieb C. W., Bleicher S. J. Coated charcoal immunoassay of insulin. J Clin Endocrinol Metab. 1965 Oct;25(10):1375–1384. doi: 10.1210/jcem-25-10-1375. [DOI] [PubMed] [Google Scholar]
- Holmes P. A., Mansour T. E. Glucose as a regulator of glycogen phosphorylase in rat diaphragm. I. Effect of glucose and related compounds on phosphorylase and glycogen levels. Biochim Biophys Acta. 1968 Mar 11;156(2):266–274. doi: 10.1016/0304-4165(68)90255-9. [DOI] [PubMed] [Google Scholar]
- Holmes P. A., Mansour T. E. Glucose as a regulator of glycogen phosphorylase in rat diaphragm. II. Effect of glucose and related compounds on phosphorylase phosphatase. Biochim Biophys Acta. 1968 Mar 11;156(2):275–284. doi: 10.1016/0304-4165(68)90256-0. [DOI] [PubMed] [Google Scholar]
- Hultman E. Muscle glycogen in man determined in needle biopsy specimens: method and normal values. Scand J Clin Lab Invest. 1967;19(3):209–217. doi: 10.3109/00365516709090628. [DOI] [PubMed] [Google Scholar]
- Jackson R. A., Roshania R. D., Hawa M. I., Sim B. M., DiSilvio L. Impact of glucose ingestion on hepatic and peripheral glucose metabolism in man: an analysis based on simultaneous use of the forearm and double isotope techniques. J Clin Endocrinol Metab. 1986 Sep;63(3):541–549. doi: 10.1210/jcem-63-3-541. [DOI] [PubMed] [Google Scholar]
- Kruszynska Y. T., Home P. D., Alberti K. G. In vivo regulation of liver and skeletal muscle glycogen synthase activity by glucose and insulin. Diabetes. 1986 Jun;35(6):662–667. doi: 10.2337/diab.35.6.662. [DOI] [PubMed] [Google Scholar]
- Kubo K., Foley J. E. Rate-limiting steps for insulin-mediated glucose uptake into perfused rat hindlimb. Am J Physiol. 1986 Jan;250(1 Pt 1):E100–E102. doi: 10.1152/ajpendo.1986.250.1.E100. [DOI] [PubMed] [Google Scholar]
- LARNER J., VILLAR-PALASI C., RICHMAN D. J. Insulin-stimulated glycogen formation in rat diaphragm. Levels of tissue intermediates in short-time experiments. Arch Biochem Biophys. 1960 Jan;86:56–60. doi: 10.1016/0003-9861(60)90367-2. [DOI] [PubMed] [Google Scholar]
- LELOIR L. F., OLAVARRIA J. M., GOLDEMBERG S. H., CARMINATTI H. Biosynthesis of glycogen from uridine diphosphate glucose. Arch Biochem Biophys. 1959 Apr;81(2):508–520. doi: 10.1016/0003-9861(59)90232-2. [DOI] [PubMed] [Google Scholar]
- Larner J., Cheng K., Schwartz C., Kikuchi K., Tamura S., Creacy S., Dubler R., Galasko G., Pullin C., Katz M. Insulin mediators and their control of metabolism through protein phosphorylation. Recent Prog Horm Res. 1982;38:511–556. doi: 10.1016/b978-0-12-571138-8.50017-2. [DOI] [PubMed] [Google Scholar]
- Le Marchand-Brustel Y., Freychet P. Regulation of glycogen synthase activity in the isolated mouse soleus muscle. Effect of insulin, epinephrine, glucose and anti-insulin receptor antibodies. Biochim Biophys Acta. 1981 Sep 18;677(1):13–22. [PubMed] [Google Scholar]
- Lillioja S., Mott D. M., Zawadzki J. K., Young A. A., Abbott W. G., Bogardus C. Glucose storage is a major determinant of in vivo "insulin resistance" in subjects with normal glucose tolerance. J Clin Endocrinol Metab. 1986 May;62(5):922–927. doi: 10.1210/jcem-62-5-922. [DOI] [PubMed] [Google Scholar]
- MORGAN H. E., PARMEGGIANI A. REGULATION OF GLYCOGENOLYSIS IN MUSCLE. 3. CONTROL OF MUSCLE GLYCOGEN PHOSPHORYLASE ACTIVITY. J Biol Chem. 1964 Aug;239:2440–2445. [PubMed] [Google Scholar]
- McGuire E. A., Helderman J. H., Tobin J. D., Andres R., Berman M. Effects of arterial versus venous sampling on analysis of glucose kinetics in man. J Appl Physiol. 1976 Oct;41(4):565–573. doi: 10.1152/jappl.1976.41.4.565. [DOI] [PubMed] [Google Scholar]
- Mott D. M., Lillioja S., Bogardus C. Overnutrition induced decrease in insulin action for glucose storage: in vivo and in vitro in man. Metabolism. 1986 Feb;35(2):160–165. doi: 10.1016/0026-0495(86)90118-6. [DOI] [PubMed] [Google Scholar]
- Nilsson L. H., Hultman E. Liver and muscle glycogen in man after glucose and fructose infusion. Scand J Clin Lab Invest. 1974 Feb;33(1):5–10. doi: 10.3109/00365517409114190. [DOI] [PubMed] [Google Scholar]
- Nuttall F. Q., Barbosa J., Gannon M. C. The glycogen synthase system in skeletal muscle of normal humans and patients with myotonic dystrophy: effect of glucose and insulin administration. Metabolism. 1974 Jun;23(6):561–568. doi: 10.1016/0026-0495(74)90084-5. [DOI] [PubMed] [Google Scholar]
- Nuttall F. Q., Gannon M. C., Bergstrom W. J. Insulin and epinephrine effects on heart glycogen synthase and phosphorylase activity. Am J Physiol. 1975 Jun;228(6):1815–1820. doi: 10.1152/ajplegacy.1975.228.6.1815. [DOI] [PubMed] [Google Scholar]
- Oron Y., Larner J. Insulin action in intact mouse diaphragm. I. Activation of glycogen synthase through stimulation of sugar transport and phosphorylation. Mol Cell Biochem. 1980 Nov 20;32(3):153–160. [PubMed] [Google Scholar]
- Radziuk J., Norwich K. H., Vranic M. Experimental validation of measurements of glucose turnover in nonsteady state. Am J Physiol. 1978 Jan;234(1):E84–E93. doi: 10.1152/ajpendo.1978.234.1.E84. [DOI] [PubMed] [Google Scholar]
- Roach R. J., Larner J. Covalent phosphorylation in the regulation glycogen synthase activity. Mol Cell Biochem. 1977 May 3;15(3):179–200. doi: 10.1007/BF01734108. [DOI] [PubMed] [Google Scholar]
- STEELE R., WALL J. S., DE BODO R. C., ALTSZULER N. Measurement of size and turnover rate of body glucose pool by the isotope dilution method. Am J Physiol. 1956 Sep;187(1):15–24. doi: 10.1152/ajplegacy.1956.187.1.15. [DOI] [PubMed] [Google Scholar]
- Tan A. W., Nuttall F. Q. Characteristics of the dephosphorylated form of phosphorylase purified from rat liver and measurement of its activity in crude liver preparations. Biochim Biophys Acta. 1975 Nov 20;410(1):45–60. doi: 10.1016/0005-2744(75)90206-5. [DOI] [PubMed] [Google Scholar]
- Thiebaud D., Jacot E., DeFronzo R. A., Maeder E., Jequier E., Felber J. P. The effect of graded doses of insulin on total glucose uptake, glucose oxidation, and glucose storage in man. Diabetes. 1982 Nov;31(11):957–963. doi: 10.2337/diacare.31.11.957. [DOI] [PubMed] [Google Scholar]
- Williams B. J., Mayer S. E. Hormonal effects on glycogen metabolism in the rat heart in situ. Mol Pharmacol. 1966 Sep;2(5):454–464. [PubMed] [Google Scholar]